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Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism.

Kain V, Kapadia B, Misra P, Saxena U - Sci Rep (2015)

Bottom Line: Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia.We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin.Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.

ABSTRACT
Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia. Recent clinical data suggest that chronic use of these drugs increases the frequency of new onset diabetes. Studies to define the risks of statin-induced diabetes and its underlying mechanisms are clearly necessary. We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin. Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway. These data may help design strategies for prevention of statin induced insulin resistance and diabetes in patients with hypercholesterolemia.

No MeSH data available.


Related in: MedlinePlus

(a) Treatment of Simvastatin builds up FFAs in muscle cells: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) followed by treatment with insulin (100 nM) for 20 min. Post treatment lipid was extracted and FFAs was estimated. Values were further normalized with the total cell count and represented as μM per million cells. *p < 0.05, versus corresponding control cells (Student’s t-test). (b) Simvastatin treatment enhances FAS, SREBP2 and ACC1 gene expression: mRNA expression of rattus FAS, SREBP2 and ACC1 in L6 myotubes treated Simvastatin (1 μM) for 48 h. *p < 0.05, **p < 0.01, versus corresponding control cells (Student’s t-test). (c) Palmitic acid mimics Simvastatin inhibited insulin mediated glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) or Palmitic acid (PA, 150 μM) for different time points as indicated. DMSO (0.1%) and BSA treated cells served as internal control. Values are shown as mean ± SD after normalizing with the corresponding protein content and expressed relative to basal of control cells (DMSO) which was set to 1; **p < 0.01, ***p < 0.005, ****p < 0.001 versus corresponding control cells (two way ANOVA). (d) Inhibition of FAS by C-75 rescues Simvastatin inhibited insulin mediated glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) and/or FAS inhibitor (C-75, 40 μg/mL) for different time points as indicated. DMSO (0.1%) served as internal control. Values are shown as mean ± SD after normalizing with the corresponding protein content and expressed relative to basal of control cells (DMSO) which was set to 1; ***p < 0.005, versus corresponding control cells, ap < 0.01, bp < 0.005 versus Simvastatin (1 μM) treated cells (two way ANOVA). (e) Inhibition of FAS by C-75 reduces FFAs in Simvastatin treated cells: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) and/or FAS inhibitor (C-75, 40 μg/mL) followed by treatment with insulin (100 nM) for 20 min. Post treatment lipid was extracted and FFAs was estimated. Values were further normalized with the total cell count and represented as μM per million cells. **p < 0.01,***p < 0.001 versus corresponding control cells, ap < 0.01, bp < 0.005 versus Simvastatin (1 μM) treated cells (two way ANOVA).
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f5: (a) Treatment of Simvastatin builds up FFAs in muscle cells: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) followed by treatment with insulin (100 nM) for 20 min. Post treatment lipid was extracted and FFAs was estimated. Values were further normalized with the total cell count and represented as μM per million cells. *p < 0.05, versus corresponding control cells (Student’s t-test). (b) Simvastatin treatment enhances FAS, SREBP2 and ACC1 gene expression: mRNA expression of rattus FAS, SREBP2 and ACC1 in L6 myotubes treated Simvastatin (1 μM) for 48 h. *p < 0.05, **p < 0.01, versus corresponding control cells (Student’s t-test). (c) Palmitic acid mimics Simvastatin inhibited insulin mediated glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) or Palmitic acid (PA, 150 μM) for different time points as indicated. DMSO (0.1%) and BSA treated cells served as internal control. Values are shown as mean ± SD after normalizing with the corresponding protein content and expressed relative to basal of control cells (DMSO) which was set to 1; **p < 0.01, ***p < 0.005, ****p < 0.001 versus corresponding control cells (two way ANOVA). (d) Inhibition of FAS by C-75 rescues Simvastatin inhibited insulin mediated glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) and/or FAS inhibitor (C-75, 40 μg/mL) for different time points as indicated. DMSO (0.1%) served as internal control. Values are shown as mean ± SD after normalizing with the corresponding protein content and expressed relative to basal of control cells (DMSO) which was set to 1; ***p < 0.005, versus corresponding control cells, ap < 0.01, bp < 0.005 versus Simvastatin (1 μM) treated cells (two way ANOVA). (e) Inhibition of FAS by C-75 reduces FFAs in Simvastatin treated cells: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) and/or FAS inhibitor (C-75, 40 μg/mL) followed by treatment with insulin (100 nM) for 20 min. Post treatment lipid was extracted and FFAs was estimated. Values were further normalized with the total cell count and represented as μM per million cells. **p < 0.01,***p < 0.001 versus corresponding control cells, ap < 0.01, bp < 0.005 versus Simvastatin (1 μM) treated cells (two way ANOVA).

Mentions: To assess our postulation, we examined if simvastatin treatment could lead to FFAs accumulation in the cells. Cells were treated with simvastatin and intracellular FFAs concentrations were estimated. As shown in Fig. 5a, FFAs levels were markedly increased by about 80% with simvastatin treatment in both control (increase from12 μM to 25 μM FFAs) and insulin treated cells (increase from 18 μM to 34 μM FFAs).


Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism.

Kain V, Kapadia B, Misra P, Saxena U - Sci Rep (2015)

(a) Treatment of Simvastatin builds up FFAs in muscle cells: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) followed by treatment with insulin (100 nM) for 20 min. Post treatment lipid was extracted and FFAs was estimated. Values were further normalized with the total cell count and represented as μM per million cells. *p < 0.05, versus corresponding control cells (Student’s t-test). (b) Simvastatin treatment enhances FAS, SREBP2 and ACC1 gene expression: mRNA expression of rattus FAS, SREBP2 and ACC1 in L6 myotubes treated Simvastatin (1 μM) for 48 h. *p < 0.05, **p < 0.01, versus corresponding control cells (Student’s t-test). (c) Palmitic acid mimics Simvastatin inhibited insulin mediated glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) or Palmitic acid (PA, 150 μM) for different time points as indicated. DMSO (0.1%) and BSA treated cells served as internal control. Values are shown as mean ± SD after normalizing with the corresponding protein content and expressed relative to basal of control cells (DMSO) which was set to 1; **p < 0.01, ***p < 0.005, ****p < 0.001 versus corresponding control cells (two way ANOVA). (d) Inhibition of FAS by C-75 rescues Simvastatin inhibited insulin mediated glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) and/or FAS inhibitor (C-75, 40 μg/mL) for different time points as indicated. DMSO (0.1%) served as internal control. Values are shown as mean ± SD after normalizing with the corresponding protein content and expressed relative to basal of control cells (DMSO) which was set to 1; ***p < 0.005, versus corresponding control cells, ap < 0.01, bp < 0.005 versus Simvastatin (1 μM) treated cells (two way ANOVA). (e) Inhibition of FAS by C-75 reduces FFAs in Simvastatin treated cells: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) and/or FAS inhibitor (C-75, 40 μg/mL) followed by treatment with insulin (100 nM) for 20 min. Post treatment lipid was extracted and FFAs was estimated. Values were further normalized with the total cell count and represented as μM per million cells. **p < 0.01,***p < 0.001 versus corresponding control cells, ap < 0.01, bp < 0.005 versus Simvastatin (1 μM) treated cells (two way ANOVA).
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Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561915&req=5

f5: (a) Treatment of Simvastatin builds up FFAs in muscle cells: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) followed by treatment with insulin (100 nM) for 20 min. Post treatment lipid was extracted and FFAs was estimated. Values were further normalized with the total cell count and represented as μM per million cells. *p < 0.05, versus corresponding control cells (Student’s t-test). (b) Simvastatin treatment enhances FAS, SREBP2 and ACC1 gene expression: mRNA expression of rattus FAS, SREBP2 and ACC1 in L6 myotubes treated Simvastatin (1 μM) for 48 h. *p < 0.05, **p < 0.01, versus corresponding control cells (Student’s t-test). (c) Palmitic acid mimics Simvastatin inhibited insulin mediated glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) or Palmitic acid (PA, 150 μM) for different time points as indicated. DMSO (0.1%) and BSA treated cells served as internal control. Values are shown as mean ± SD after normalizing with the corresponding protein content and expressed relative to basal of control cells (DMSO) which was set to 1; **p < 0.01, ***p < 0.005, ****p < 0.001 versus corresponding control cells (two way ANOVA). (d) Inhibition of FAS by C-75 rescues Simvastatin inhibited insulin mediated glucose uptake: Mean basal and insulin stimulated (5 min and 10 min) uptake of 2-NBDG by L6 myotubes treated with Simvastatin (1 μM) and/or FAS inhibitor (C-75, 40 μg/mL) for different time points as indicated. DMSO (0.1%) served as internal control. Values are shown as mean ± SD after normalizing with the corresponding protein content and expressed relative to basal of control cells (DMSO) which was set to 1; ***p < 0.005, versus corresponding control cells, ap < 0.01, bp < 0.005 versus Simvastatin (1 μM) treated cells (two way ANOVA). (e) Inhibition of FAS by C-75 reduces FFAs in Simvastatin treated cells: L6 myotubes were cultured for 48 h in presence of Simvastatin (1 μM) and/or FAS inhibitor (C-75, 40 μg/mL) followed by treatment with insulin (100 nM) for 20 min. Post treatment lipid was extracted and FFAs was estimated. Values were further normalized with the total cell count and represented as μM per million cells. **p < 0.01,***p < 0.001 versus corresponding control cells, ap < 0.01, bp < 0.005 versus Simvastatin (1 μM) treated cells (two way ANOVA).
Mentions: To assess our postulation, we examined if simvastatin treatment could lead to FFAs accumulation in the cells. Cells were treated with simvastatin and intracellular FFAs concentrations were estimated. As shown in Fig. 5a, FFAs levels were markedly increased by about 80% with simvastatin treatment in both control (increase from12 μM to 25 μM FFAs) and insulin treated cells (increase from 18 μM to 34 μM FFAs).

Bottom Line: Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia.We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin.Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.

ABSTRACT
Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia. Recent clinical data suggest that chronic use of these drugs increases the frequency of new onset diabetes. Studies to define the risks of statin-induced diabetes and its underlying mechanisms are clearly necessary. We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin. Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway. These data may help design strategies for prevention of statin induced insulin resistance and diabetes in patients with hypercholesterolemia.

No MeSH data available.


Related in: MedlinePlus